Many cytokines are known as humoral factors involved in the growth and differentiation of various types of cells, or in the activation of differentiated mature cell functions. Cytokine-stimulated cells produce different types of cytokines, thereby forming networks of multiple cytokines in the body. Biological homeostasis is maintained by a delicate balance of the mutual regulation between cytokines in these networks. Many inflammatory diseases are thought to result from a failure of such cytokine networks. Thus, monoclonal antibody-based anti-cytokine therapy is drawing much attention. For example, anti-TNF antibodies and anti-IL-6 receptor antibodies have been demonstrated to be highly effective clinically. On the other hand, there are many examples of failure where no therapeutic effects were produced when a single cytokine, such as IL-4, was blocked alone, due to the activation of compensatory pathways in actual pathological conditions.
The present inventors succeeded in isolating a novel cytokine receptor NR10 that was highly homologous to gp130, a receptor for IL-6 signal transduction (Patent Document 1). NR10 forms a heterodimer with oncostatin M receptor (OSMR) and functions as an IL-31 receptor (Non-patent Document 1). NR-10 is also known as glm-r (Non-patent Document 2), GPL (Non-patent Document 3), IL-31RA (Non-patent Document 4), and such. It has also been reported that transgenic mice overexpressing IL-31 spontaneously develop pruritic dermatitis (Non-patent Document 4).
However, it cannot be asserted that forced cytokine expression in mice or a high concentration of blood cytokine in pathological mice are actual causes of the disease. It is totally unclear whether signal blockage by an antibody produces a therapeutic effect. For example, transgenic mice in which IL-18 is overexpressed in keratinocytes develop pruritic dermatitis. In spontaneous atopic dermatitis model mice NC/Nga, the blood concentration of IL-18 increases with advancement of the pathological conditions. From these findings, the overexpression of IL-18 was presumed to be a cause of the disease. Actually, however, the administration of a neutralizing antibody exhibited no therapeutic effect (Non-patent Document 5).
Thus, the inhibition of cytokine function does not necessarily produce a therapeutic effect in diseases with elevated cytokine expression. It is thus difficult to predict from the expression level of a cytokine what disease the inhibition of the cytokine produces a therapeutic effect on. Therefore, it is important to identify diseases on which the inhibition of signaling of a target cytokine actually produces a therapeutic effect.
Prior art documents of the present invention are described below:    Patent Document 1: WO00/75314    Non-patent Document 1: IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis., J Allergy Clin Immunol. 2006 February; 117(2):418-25.    Non-patent Document 2: A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. J Biol Chem 277, 16831-6, 2002    Non-patent Document 3: GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor. J Biol Chem 278, 49850-9, 2003    Non-patent Document 4: Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5, 752-60, 2004    Non-patent Document 5: Administration of anti-interleukin 18 antibody fails to inhibit development of dermatitis in atopic dermatitis-model mice NC/Nga., British Journal of Dermatology 149: 39-45, 2003